PROJECT SUMMARY Development of a mind body program to reduce cartilage breakdown and knee pain in obese osteoarthritis patients with comorbid depression This is a R34 application that follows the recently released IMMPACT criteria, and the International Classification of Functioning, Disability and Health (ICF) framework to adapt a multimodal, theory grounded mind body program (The Relaxation Response Resilience Program; 3RP) with prior success in patients with medical illness in pilot and effectiveness studies for the needs of obese patients with knee osteoarthritis (OA) and depression and to specifically target increased physical activity (p3RP-OA). Depression, obesity and OA exacerbate one another and share a common pathophysiology involving systemic inflammation and pro- inflammatory cytokines, reflecting a complex mind-body interaction. Current treatments for knee OA offer little to no benefit over a placebo, and do not emphasize mind-body practices or physical activity to target the underlying pathophysiology. Physical activity alone has shown benefit in the treatment of depression, obesity and OA individually, but adequate implementation remains challenging. Our guiding hypothesis is that the synergistic interaction between mindfulness, adaptive thinking, positive psychology and healthy living skills of the 3RP adapted for the needs of OA patients and to target increased physical activity reduces pro- inflammatory cytokine expression while also promoting optimal mechanical loading of the cartilage will slow the progression of symptomatic knee OA. Toward this goal, this R34 proposal aims to 1) adapt the 3RP for the needs of knee OA patients with depression (PHQ-9?10) and obesity (BMI?30 kg/m2) with a focus of increasing physical activity; and 2) establish the feasibility, credibility and acceptability of the programs and research procedures. Using the R34 NCCIH mechanism, we propose to use an iterative mixed methods strategy to adapt the 3RP for the specific needs of obese OA patients with depression including increased activity to maximize their feasibility, acceptability, and credibility. This R34 grant will set the stage for us to conduct a fully powered RCT through the R61/R33 mechanisms to assess the biopsychosocial mechanisms associated with OA progression.